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Research Papers

Single-Cell Migration in Complex Microenvironments: Mechanics and Signaling Dynamics

[+] Author and Article Information
Michael Mak, Fabian Spill

Department of Mechanical Engineering,
Massachusetts Institute of Technology,
77 Massachusetts Avenue,
Cambridge, MA 02139;
Department of Biomedical Engineering,
Boston University,
44 Cummington Mall,
Boston, MA 02215

Roger D. Kamm

Department of Mechanical Engineering,
Department of Biological Engineering,
Massachusetts Institute of Technology,
77 Massachusetts Avenue,
Cambridge, MA 02139
e-mail: rdkamm@mit.edu

Muhammad H. Zaman

Department of Biomedical Engineering,
Boston University,
44 Cummington Mall,
Boston, MA 02215;
Howard Hughes Medical Institute,
Boston University,
Boston, MA 02215
e-mail: zaman@bu.edu

1Contributed equally to this work.

2Corresponding author.

Manuscript received September 23, 2015; final manuscript received November 25, 2015; published online January 27, 2016. Editor: Victor H. Barocas.

J Biomech Eng 138(2), 021004 (Jan 27, 2016) (8 pages) Paper No: BIO-15-1478; doi: 10.1115/1.4032188 History: Received September 23, 2015; Revised November 25, 2015

Cells are highly dynamic and mechanical automata powered by molecular motors that respond to external cues. Intracellular signaling pathways, either chemical or mechanical, can be activated and spatially coordinated to induce polarized cell states and directional migration. Physiologically, cells navigate through complex microenvironments, typically in three-dimensional (3D) fibrillar networks. In diseases, such as metastatic cancer, they invade across physiological barriers and remodel their local environments through force, matrix degradation, synthesis, and reorganization. Important external factors such as dimensionality, confinement, topographical cues, stiffness, and flow impact the behavior of migrating cells and can each regulate motility. Here, we review recent progress in our understanding of single-cell migration in complex microenvironments.

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Figures

Grahic Jump Location
Fig. 1

Growth factors (GF), ECM ligand binding, or mechanical stimuli through integrins initiate an intracellular signaling cascade, which leads to regulation in actin and myosin activity. The molecules and interactions shown here are only a small selection of the full cascades, focusing on some key players which are necessary to regulate directed cell migration.

Grahic Jump Location
Fig. 2

Time evolution of active Cdc42 on the membrane for two cells. The top row shows a symmetric cell which loses polarization quickly after an initial stimulus at the front. The cell in the bottom row, which is very thin in the center, stays permanently in a polarized state. Both cells have the same length (40 μm) and would hence appear identical in a 1D model, confirming that their 3D shape plays an important role in determining their polarization state. All simulations were performed with the 3D reaction–diffusion model described by Spill et al. [57].

Grahic Jump Location
Fig. 3

Schematic of various signals in the 3D microenvironment. A cell migrating in physiological environments may be subject to numerous cues, including small pores that require deformation of the nucleus, aligned ECM fibers, interstitial flow through the porous ECM, and gradients of chemotactic factors (gradient profile).

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